Chemistry of Linkers in Antibody-Drug Conjugates (ADCs): Design, Clinical Trends, and Future Perspectives

Antibody-drug conjugates (ADCs) have significantly advanced the field of targeted cancer therapy by enabling the precise delivery of cytotoxic agents to tumor cells through monoclonal antibodies. Among the key components of ADCs, the linker plays a crucial role in maintaining the stability of the conjugate in systemic circulation and ensuring the controlled release of the payload at the tumor site. These functions critically influence both the therapeutic efficacy and safety profile of ADCs. Linkers can generally be categorized into two main types: cleavable and non-cleavable. Cleavable linkers include those that are sensitive to acidic pH, specific proteases, or redox conditions (such as disulfide bonds). These linkers facilitate selective drug release within the tumor microenvironment. In contrast, non-cleavable linkers, such as thioethers, require intracellular degradation for drug release and typically provide greater stability in plasma. From a clinical perspective, cleavable peptide-based linkers, especially valine-citrulline (Val-Cit), are widely used in approved ADCs including Brentuximab vedotin and Polatuzumab vedotin. These linkers allow for tumor-specific drug release. On the other hand, non-cleavable linkers, as exemplified by Trastuzumab emtansine, offer enhanced systemic stability but rely on lysosomal degradation of the antibody component for payload liberation. Recent technological advances have focused on improving the precision and functionality of ADCs through site-specific conjugation techniques (such as THIOMABS engineered with cysteine residues), as well as the use of self-immolative spacers like para-aminobenzyl carbamate (PABC). These spacers undergo spontaneous decomposition after linker cleavage, which leads to the efficient release of the active drug. Furthermore, microenvironment-responsive linkers have been developed to exploit unique tumor conditions, including low pH, hypoxia, or specific enzymatic activity (for example, legumain-sensitive linkers). Despite these innovations, challenges such as structural heterogeneity of ADCs and premature drug release remain. Future strategies aim to overcome these limitations by employing next-generation multifunctional linkers, dual-payload delivery systems, the incorporation of hydrophilic chaperones, and the integration of artificial intelligence and machine learning in linker design. These approaches collectively seek to broaden the therapeutic window and improve clinical outcomes for cancer patients.

کلیدواژه ها:

Antibody-Drug Conjugate (ADC) ، linker ، cleavable ، noncleavable